Mercapto benzothiazole compounds



2,777,853 MERCAPTO BENZOTI HAZOLE COMPOUNDS Norbert Steiger, Nntley,

La Roche Inc Nutley, Jersey N. J., assignor to Holfmann- N. 3., acorporation of New No Drawing. Application September 6, 1955, Serial No.532,768

9 Claims. (Cl. 260-306) I I C- S CR4 III-lower alkylene-O- S halogenwherein NRIRZ represents a dilower alkylamino group or aheteromonocyclic radical having to 6 atoms in the ring, R3 representshydrogen or a lower alkyl group, and R4 represents hydrogen or an alkylor an aryl group.

The heteromonocyclic radicals represented by NR1R2 include saturated,nitrogen-containing heterocyclic groups such as piperidino, morpholino,pyrrolidino and the like. The term lower alkylene used in the abovestructural formula refers to straight chain and branched chain divalentlower aliphatic radicals, preferably those containing 1 to 5 carbonatoms in the chain. Aryl groups within the meaning of the above formulainclude monocyclic substituted and unsubstituted aromatic radicals suchas phenyl, benzyl, halogen-substituted phenyl or benzyl, etc. Alkylgroups represented by R4 include straight chain and branched chaingroups having up to about 12 carbon atoms such as methyl, ethyl, propyl,

lower alkyl-O s Patent 0 lower alkyl-O- 0-8- (a-Halogen alkyl)isopropyl, butyl, amyl, decyl and the like. A most preferred class ofcompounds constitutes the group wherein R3 represents hydrogen and R1,R2 and R4 each represents a lower alkyl group.

It is to be noted that the halogen atom in the compounds represented bythe above formula is on the carbon atom on to the mercapto sulfur atomand this conguration is hereinafter referred to by the terms Ot'haiO orct-halogen.

Compounds of the invention represented by the above formula are basesand readily form acid addition salts with inorganic and organic acids,e. g. mineral acids such as hydrochloric, hydrobromic, hydriodic,sulfuric and phosphoric acids, acetic acid, tartaric acid, oxalic acid,citric acid, ethanesulfonic acid, toluenesulfonic acid and the like.They also form quaternary ammonium salts with acyclic and cyclicquaternizing agents such as lower alkyl halides (e. g. methyl bromide,ethyl iodide, n-butyl chloride), di(lower alkyl) sulfates (e. g.dimethyl sulfate), aralkyl halides (e. g. benzyl bromide, p-chlorobenzylbromide), and the like. Since the bases having the above formula may bemonoacidic or polyacidic bases, the salts formed by these bases includethe monoand poly-acid addition salts and monoand polyquaternary salts.The invention includes within its scope the bases having the abovedescribed formula and acid addition salts and quaternary ammonium saltsof those bases. A particularly preferred class of salts constitutes thepharmaceutically acceptable salts formed by the bases with the non-toxicacids and quaternizing agents conventionally employed in the preparationof therapeutic substances.

The compounds of this invention are useful as antifungal andanti-protozoan agents, more particularly they are useful as the activemedicament in pharmaceutical formulations for treating the infectionscaused by the organisms T richophyton mentagrophytes, Microsporonlanosum, Candida albicans and T richomonas vaginalis. The therapeuticagents of this invention may be administered in therapeutic dosestopically, e. g. in conventional vehicles in the form of ointments orcreams.

The new compounds are prepared according to the following illustrativegeneral reaction scheme:

0-S-alkyl in ethanol or acetic acid HBr (48% aqueous) HzSO; (00110.) at2550 [or CISOgH at 1020] dilower alkylamino alkyl halide or piperldinoalkyl halide or pyrrolidino alkyl halide (4) or morpholino alkyl halide,etc.

F 0-8 -CAlky1 alogen lower alkyl N-alkylene-O lower alkyl Whenchlorosulfonic acid is used in treating the alkylsulfinylbenzothiazole,steps (2) and (3) above may be combined.

Alternatively, the 6-l0wer alkoxy-2-(a-halogenalkylmercapto)benzothiazoles may be obtained by treating a 6-loweralkoxy-Z-alkylmercapto benzothiazole with sulfuryl chloride in a solventsuch as methylene chloride at about 40 then proceeding as in steps (3)and (4) above.

Acid addition salts of the bases formed according to the above methodare produced by reacting the base with the appropriate inorganic ororganic acid. if desired, the acid addition salt may first be isolatedand then converted to the base by dissolving the acid addition salt in asolvent such as water, neutralizing with a strong base, for example,sodium hydroxide, and extracting the base with ether or benzene. Thebases may be recovered from the solvent by distilling in vacuo.Quaternary ammonium salts are produced by reacting the base with aquaternizing agent such as alkyl halides aralkyl halides, etc.

The following examples are illustrative of the invention. Alltemperatures are expressed in degrees centigrade.

Example 1 105 grams (0.5 mol) of 2 mercapto 6 ethoxybenzothiazole weredissolved in 100 cc. of 40% sodium hydroxide and 500 cc. of water. 60cc. of'dimethyl sulfate were dropped in with agitation at a temperaturebelow 45. The mixture was heated for one hour at 70, then cooled to 20.The 2-methyl-mercapto-6- ethoxy -benzothiazole thus obtained wasfiltered and washed on the funnel with cold water. The material wasdried overnight on the filter funnel.

204 grams (0.91 mol) of Z-methylmercapto-6-ethoxybenzothiazole wererefluxed with 2000 cc. of alcohol and 200 cc. of hydrogen peroxide (30%)for 8 hours. The mixture was chilled to then the 2-methylsulfinyl-6-ethoxy-benzothiazole was filtered and dried on the filter funnel.

162 grams of Z-methylsulfinyl-G-ethoxy-benzothiazole were added withstirring to 240 cc. of thionyl chloride below 15. The mixture wasstirred for 3 hours at room temperature and then drowned in ice.Crystalline 2- chloromethylmercapto-6-ethoxy-benzothiazole was thusobtained. The compound was stirred for 2 hours, filtered and washed acidfree with cold water. The crystals were dried overnight. The compoundwas crystallized from 700 cc. of alcohol. The 2-chloromethylmercapto-6ethoxy-benzothiazole melts at 108l10 C.

116 grams of 2-chloromethylmercapto-6=ethoxy-benzothiazole weredissolved in 600 cc. of sulfuric acid (94%) at below 15. After stirringat room temperature for one hour, the mixture was heated in a water bathat 50 for one hour and left standing overnight. The mixture was thentrickled by dropping funnel into a battery jar containing ice and water.The solid white precipitate which formed was filtered and washed withice water. The filter cake was dissolved at 50 in 60 cc. of sodiumhydroxide and 1500 cc. of water. The mixture was filtered through adiatomaceous earth coated funnel. acidified with 45 cc. of acetic acid.The precipitate which The filtrate was drying over sodium sulfate, wasconcentrated in vacuo. The2-chloromethylmercapto-6-(fi-diethylaminoethoxy)- benzothiazole thusobtained was dissolved in 600 cc. of ether, filtered, chilled .to 10 andprecipitated with 70 cc. of ethanol-HCl (35%). The precipitate wasfiltered, washed with ether, and dried over sodium hydroxide in adesiccator. The2-chloromethylmercapto-6-(fl-diethylaminoethoxy)benzothiazole'hydrochloride was recrystallized from acetone-alcohol, M. P. 162.

37 grams of2-chloromethylmercapto-6-(fi-diethylaminoethoxy)-benzothiazolehydrochloride were dissolved in 500 cc. of water at 50. The clearsolution was chilled to 10-15" and 105 cc. of N sodium hydroxidesolution were added. The free base precipitated as an oil whichcrystallized upon standing in the refrigerator. The white crystals thusobtained were filtered and washed with ice water. The crystals were thendried in the desiccator over sodium hydroxide, M. P. 53.

6 grams of the base obtained in the preceding paragraph were dissolvedin 70 cc. of acetone. To this solution was added a solution of 4.2 gramsof citric acid in 10 cc. of alcohol. The2-chloromethylmercapto-6-(fldiethylaminoethoxy)benzothiazole citratewhich crystallized was filtered, washed with acetone and recrystallizedfrom alcohol-acetone, M. P. 150".

Example 2 113 grams (0.47 mol) of 2-mercapto-6-ethoxy-benzothiazole werestirred in a 2-liter, 3-necked flask in a solution of 500 cc. of waterand 100 cc. of sodium hydroxide 76 grams of ethyl bromide dissolved in100 .cc. of alcohol were trickled into the water solution. The mixturewas heated to until it showed a negative test to lead acetate. Thealcohol was then distilled off at 80-85 The mixture was chilled to 20,whereupon 2- ethylmercapto-6-ethoxy-benzothiazole crystallized. Thecrystals were filtered, washed with water and dried on the funnel bysuction.

125 grams of Z-ethyhnercapto-6-ethoxy-benzothiazole were refluxed in a3-liter, 3-necked flask with 1000 cc. of alcohol and 150 cc. of hydrogenperoxide (30%) for 8 hours. About two-thirds of the alcohol weredistilled ofl in vacuo. The concentrate was diluted with 6 to 7 litersof ice water to obtain a crystalline precipitate. The2-ethylsulfiuyl-6-ethoxy-benzothiazole was filtered, dried on the funneland then crystallized from 500 cc. of an n-heptane hydrocarbon fraction.

115 grams (0.45 mol) of 2-ethylsulfinyl-6-ethoxybenzothiazole were addedto 125 cc. of thionyl chloride in a l-liter, 3-necked flask whilecooling below 15. The mixture was stirred for 2 hours at roomtemperature, then drowned in ice and water.2-(ct-chloroethylmercapto)-6- formed was filtered and washed twice withice water. The

Z-chIoromethylmercapto 6 hydroxy-benzothiazole was dried on the filterfunnel and finally dried in the oven, M. P. 117-119".

In a 2-liter, 3-neclred flask there were charged 102 grams of2-chloromethylmercapto-fi-hydroxy-benzothiazole, 800 cc. ofchlorobenzene, 140 cc. of methanol and 34 grams of sodium methoxide. Themethanol was distilled oil and 75 cc. of [B-diethylaminoethyl chlorideand 70 cc. of chlorobenzene were added at 100. The mixture was refluxedfor 4 hours. 500 cc. 'of water and 25 cc. of sodium hydroxide were thenadded. The layers which formed were separated and thechlorobenzenelayer, after ethoxy-benzothiazole crystallized out. Thecrystals were filtered, washed with ice water, dried on the funnel, thenrecrystallized from 250 cc. of alcohol, M. P. 62-64".

45 grams of 2-(a-chloroethylmercapto)-6-ethoxy-benzothiazole were addedat 5-l0 to 200 cc. of chlorosulfonic acid in a 3-necked flask. Themixture was stirred for 2 hours at 20 and then drowned by dropping intoice and water from a dropping funnel. After standing overnight thecrystalline compound which formed was filtered and washed with icewater. The crude product was dissolved at 50 in 50 cc. of sodiumhydroxide (40%), and 1300 cc. of water and filtered. The filtrate wascooled to 20 and acidified with 40 cc. of acetic acid. The crystallineprecipitate, 2-(a-chloroethylmercapto)-6-hydroxybenzothiazole, wasfiltered, washed with ice water and dried .in an oven at 75, M. P.126-128".

35 grams (0.143 mol) of 2-(a-chloroethylmercapto)-6-hydroxy-benzothiazole, 350 cc. of chlorobenzene, 12 grams of sodiummethoxide and 50 cc. of methanol were stirred in a 3-necked flask. Themethanol was then distilled off and distillation was continued until thetemperature reached 130". 25 cc. of B-diethylaminoethyl chloride wereadded at and the mixture was refluxed at 130 for 4 hours. Then cc. ofsodium hydroxide (40%) and 250 cc. of water were added at 100. Themixture was stirred for one-half hour and the layers which formed uponstanding were separated in a separatory funnel. The chlorobenzene layer,after drying over sodium sulfate, was concentrated in vacuo.2-(u-Chl01'0- ethylmercapto)-6-(;9 diethylaminoethoxy)benzothiazole wasthus obtained as an oil.

The oil obtained above was dissolved in 300 cc. of ether and filtered.The filtered ether solution was chilled to 10 and 30 cc. of ethanol-H01(35%) was added. 2-(a-chloroethylmercapto) 6 S-diethylaminoethoxy)-benzothiazole hydrochloride precipitated as a white crystalline powderwhich was filtered on a fritted funnel and dried in a desiccator. Theproduct was recrystallized from 500 cc. of acetone and 120 cc. ofalcohol, M. P. 170-471.

Example 3 242 grams (1 mol) of 2-ethylrnercapto-6-ethoxy-benzothiazolewere dissolved in 600 cc. of methylene chloride. 150 grams of sulfurylchloride dissolved in 150 cc. of methylene chloride were dropped intothe solution at 40. The mixture was refluxed for 45 minutes and themethylene chloride was then distilled ofi. To the residue were added 500cc. of ethanol and the mixture was heated to reflux for minutes. Theclear solution obtained was filtered hot. The filtrate was chilled and 2(cc chloroethylmercapto) 6 ethoxy benzothiazole crystallized.

204 grams of 2 (oz chloroethylmercapto) 6 ethoxybenzothiazole weredissolved in 850 cc. of concentrated sulfuric acid at room temperature,then heated 5 hours at 45 to 50. The reaction mixture was then drownedin 12 liters of ice and water. The solid was filtered off and dissolvedin 2000 cc. of water and 80 cc. of 40% sodium hydroxide at 50. 15 gramsof charcoal were added and the mixture was filtered. The filtrate waschilled to acidified with 60 cc. acetic acid, filtered and dried toobtain 6 hydroxy 2 (a chloroethylmercapto) benzothiazole as whitecrystals.

151.5 grams of the compound prepared above, 1100 cc. of chlorobenzene,42 grams of sodium methoxide and 170 cc. of methanol were heated andstirred. The methanol was allowed to distill off until the temperaturereached 131. 130 cc. of ,B-diethylaminoethyl chloride were added at 100and the mass was refluxed 4 hours at 130 to 132". 600 cc. of water and30 cc. of sodium hydroxide were added at a temperature below 100 and themixture was stirred 30 minutes. The chlorobenzene layer was separated,dried with sodium sulfate and concentrated in vacuo to obtain 2 (achloroethylmercapto)- 6 (13 diethylaminoethoxy) benzothiazole as an oil.

34.5 grams of the base obtained above were dissolved in 250 cc. ofacetone. To the solution were added at 0 a solution of 22 grams ofcitric acid in 30 cc. of alcohol. The citrate, crystallized fromethanol, melted at 142-143 Example 4 25 grams (0.1 mol) of 2 (achloroethylmercapto)- 6 hydroxybenzothiazole were suspended in 350 cc.of chlorobenzene. 8 grams of sodium methoxide and 100 cc. of methanolwere then added and the mixture was distilled until the temperaturereached 131. After cooling to room temperature, 150 cc. of chlorobenzeneand 19 grams of freshly prepared dimethylaminoisopropyl chloride wereadded. The reaction mixture was refluxed at 131 for 3%. hours, thencooled to 85. 20 cc. of 40% sodium hydroxide in 150 cc. of water wereslowly added. After one-half hour of stirring, the mixture was permittedto settle and the chlorobenzene phase was sep arated then dried withsodium sulfate. On removal of the solvent by vacuum distillation on asteam bath, the oily base, 2 1 chloroethylmercapto) 6 (2dimethylaminoisopropoxy)benzothiazole, was purified by refluxed at 132for 3 /2 hours.

high vacuum distillation, B. P. 178-181 at 0.01 mm. of Hg.

The base was converted to the hydrochloride by dissolving it in ethylacetate, adding ethanol-HCl while cooling, then diluting it with ether.The hydrochloride melted at 168170 C. upon recrystallization from ethylacetate-ethanol.

Example 5 25 grams (0.1 mol) of 2 (a chloroethylmercapto)- 6hydroxybenzothiazole were suspended in 350 cc. of chlorobenzene. 8 grams(0.15 mol) of sodium methylate, followed by 100 cc. of methanol, wereadded. The mixture was distilled until the temperature reached 132, thenallowed to cool to 50. 22 grams (0.15 mol) of freshly prepared ,8 (Npiperidyl)ethyl chloride were added and the reaction mixture wasrefluxed at 132 for 3 /2 hours. After cooling to 20 cc. of 40% sodiumhydroxide in 150 cc. of water were slowly added and the mixture wasstirred for one-half hour. After settling, the chlorobenzene phase wasseparated and dried with sodium sulfate. The solvent was removed byvacuum distillation on a steam bath and the 2 (1 chloroethylmercapto) 6[2 (1 piperidyl)ethoxy]benzothiazole was purified by distillation invacuo, B. P. 205213 at 0.02 mm. of Hg.

The hydrochloride was prepared by dissolving the base in ethyl acetate,cooling, adding ethanolic hydrochloric acid and diluting with ether, M.P. 165168.

Example 6 25 grams (0.1 mol) of 2 (0c chloroethylmercapto)-d-hydroxybenzothiazole were suspended in 350 cc. of chlorobenzene. 8grams of sodium methylate and cc. of methanol were added. The mixturewas distilled until the temperature reached 132 and then permitted tocool to room temperature. 100 cc. of chlorobenzene and 20 grams (0.15mol) of freshly prepared 18 (N- pyrrolidino)ethyl chloride were added.The mixture was refluxed at 132 for 3 /2 hours. After cooling to 80, :1solution of 20 cc. of 40% sodium hydroxide in cc. of water was added andthe mixture was stirred for onehalf hour. The chlorobenzene layer whichformed upon standing was separated and dried with sodium sulfate. Thesolvent was removed by vacuum distillation on a steam bath to obtain theoily base, 2 (1 chloroethylmercapto) 6 [2 (1 pyrrolidyl)ethoxy]benzothiazole.

The oily base obtained above was converted to the hydrochloride bydissolving it in ether and treating with gaseous hydrogen chloride. Thehydrochloride melted at 183-185 upon recrystallization from ethylacetate-ethanol-ether.

Example 7 25 grams (0.1 mol) of 2 (a chloroethylmercapto)-6-hydroxybenzothiazole were suspended in 350 cc. of chlorobenzene. 8grams of sodium methoxide and 100 cc. of methanol were added, themixture was distilled until the temperature reached 131 and was thenpermitted to cool to 50. 150 cc. of chlorobenzene were added, followedby 21 grams (0.14 mol) of freshly prepared 3chloropropyl-N-diethylamine. The reaction mixture was After cooling to85, a solution of 20 cc. of 40% sodium hydroxide in 150 cc. of water wasslowly added and the mixture was stirred for one-half hour. Aftersettling, the reaction mixture was transferred to a separatory funneland the chlorobenzene layer was drawn off. The chlorobenzene layer wasdried with sodium sulfate. for 3 hours. The filtered solution wasconcentrated in vacuo on a steam bath to obtain an oil which was thendistilled in high vacuum to give the aminopropoxy) benzothiazole, B. mm.of Hg.

P. l86-190 at 0.01

The hydrochloride of the base obtained above was produced by dissolving25 grams (0.070 mol) of the base in 200 cc. of lethyl' acetate. To thecooled solution 20 cc. ofa 35 solution of hydrogen chloride gas inethanol were slowly added, followed by 75 cc. of ethanol. On dilutionwith 100 cc. of ether, the hydrochloride precipitated. Uponrecrystallization from ethyl acetate-ethanol, the hydrochloride meltedat 143445 Example 8 91 grams of Z-ethylsulfinyl-6-ethoxy-benzothiazolewere stirred in a 3-necked flask with 300 cc. of 48% hydrogen bromide at939S for 8 hours. The mixture was chilled to 10 and the crystallineprecipitate which formed was filtered on a fritted glass funnel. Thefilter cake was sludged with 500 cc. of water, stirred for one hour andfiltered. The filter cake was then crystallized from a mixture of 500cc. of alcohol and 50cc. of water. The crystals obtained wereheated andstirred with 250 cc. oi 48% hydrogen bromide for 6 hours in a 3-neckedflask equipped with a reflux condenser. The contents of the flask werediluted with 300 cc. of'salt water (30%) at 20, filtered and washed-withsalt water. The filter cake was dissolved in 1500 cc. of water and 50cc. of sodium hydroxide at 70. The solution was filtered fromalkaliinsoluble material which was present. The filtrate was at roomtemperature and recrystallized from 600 cc. of an n-heptane hydrocarbonfraction.

106 grams of Z-isopropylsulfinyl-6-ethoxy-benzothiazole were dissolvedin 170 cc. of thionyl chloride at 1020 and the mixture was stirred 1%hours at room temperature. The mixture was drowned in ice and water,stirred one hour and the solid was then filtered oil". The filter cakewas dissolved in 200 cc. of alcohol at 70 to 75. The solution was cooledin a refrigerator, whereupon 2 (on chloroisopropylmercapto) 6 ethoxybenzothiazole crystallized, M. P. 54".

81.5 grams of 2-(u-chloroisopropylmercapto)-6-ethoxybenzothiazole weredissolved in 500 cc. of sulfuric acid (94%) at 5 to The solution wasstirred first at room temperature for 2 hours, then at 50 for 3 hours.After standing overnight at room temperature, the solution was pouredonto ice andwater. Crude Z-(oc-ChlOl'O- isopropylmercapto) 6 hydroxybenzothiazole precipitated as a semi-solid mass. The crude product wasdecanted, dissolved in 60 cc. of sodium hydroxide and 2000 cc. of waterat 50, then filtered. The filtrate was acidified with acetic acid atZ-(cc-bIOIIlOEthYlIIlBI- capto) 6 hydroxy bcnzothiazole precipitated aswhite crystals. The product was filtered and dried at 75.

44 grams of 2-(u-bromoethylmercapt0) -6-hydroxy-benzothiazole, 500 cc.of chlorobenzene, 16 grams of sodium methoxide and 60 cc. of methanolwere heated in a 3- necked flask for one hour at 65 to 70. The methanolwas then distilled off until the temperature in the flask reached 130.45 grams of e-diethylaminoethyl chloride were added at 100 and themixture was refluxed with stirring for 4 hours at 130. The mixture wasdiluted with 300 cc. of water and 10 cc. of sodium hydroxide below 100.After settling, the chlorobenzene'layer was separated, dried with sodiumsulfate and concentrated in vacuo. 2 (u bromoethylrnercapto) 6 (ediethylaminoethoxy)benzothiazole was collected as an oil. The oilobtained above was dissolved in 300 cc. of ether. The solution waschilled to 0 and precipitated with cc. of ethanol-H01 (35 The whitecrystalline Z-(oc-blO- moethylmercapto) 6 (tidiethylaminoethoxy)benzothiazole hydrochloride --was filtered, dried andrecrystallized from alcohol-acetone, M. P. 162163.

Example 9 .4 grams .of 2-(chloromethylmercapto):6 (ediethyhaminoethoxy)benzothiazole (prepared according to the procedure describedin Example vl) were dissolved in 25 cc. of acetone. 3.0% solution ofmethyl bromide in acetone at 15. Off- White crystals ofZ-chloromethylmercapto-6-(d-diethylamiuoethoxy)benzothiazole-methylbromide, M. P. 175", crystallized upon standing overnight in therefrigerator.

7 Example 10 half its-volume andtheconcentrate was poured into 7000 cc.of ice water. The -2-isopropylsulfinyl-6-ethdxydzenzothiazole whichcrystallized out was then filtered, dried To the' solution were added 6cc. of a .hours at room temperature.

isopropylmercapto)-6-hydroxybenzothiazole settled as a heavy oil. Theoil was decanteidissolved in 400 cc. of alsohol and concentrated invacuo.

57 grams of 2-(a-chloroisopropylmercapto)-6-hydroxybenzothiazole weredissolved in cc. of methanol and 500 cc. of chlorobenzene. 16 vgramsof'sodium methoxide were added. The mixture was stirred and heated, thenthe methanol was distilled 00?. 40 cc. of ,B-diethylaminoethyl chloridewere added at 100 and the mixture was refluxed for 4 hours. 400 cc.of'water and 15 cc. of sodium hydroxide were added at 100 and stirredfor one-half hour. After settling, the chlorobenzene layer was separatedand concentrated in vacuo to obtain Z-(otchloroisopropylmercapto) .6 (Bdiethylaminoethoxy)- benzothiazole.

The base thus obtained was dissolved'in 600 cc. of ether andprecipitated at 5 with 70 cc. of ethanol-HCI (35%). The2-(a-chloroisopropylrnercapto)-6-(;8-diethylaminoethoxy)benzothiazolehydrochloride was filtered on a fritted funnel, dried in a desiccatorwith sodium hydroxide and then recrystallized from acetone-alcohol, M.P. 164-166".

Example 11 grams (0.5 mol) of Z-mercaptO-o-ethoxy-benzothiazole weredissolved in 50.0 cc. of water and 100 cc. of sodium hydroxide (40%).The solution was heated with 80 grams of n-butyl bromide dissolved in200 cc. :of alcohol for one hour at reflux temperature (80). The alcoholwas distilled off and 2-n-butylmercapto-6-ethoxybenzothiazole separatedas an .oil. 127 grams of the .thioether thus obtained were refluxed for8 hours with 1000 cc. of alcohol and cc. .of hydrogen peroxide .(-30%.).The alcoholic solution was then concentrated in vacuo to one-half itsvolume. The concentrate was poured into 6000 cc. of ice water. Crude2-n-butylsulfinyl-6-ethoxybenzothiazole precipitated in crystallineform. The crystals were filtered, dried on the funnel and recrystallizedfrom 500 cc. of an n-heptanehydrocarbon fraction. The melting point ofthe pure product was 64-67 76 grams of2-nbutylsulfinyl-d-ethoxy-benzothiazole were dissolved in 100 cc. ofthionylchloride below 15 with stirring and cooling. Thesolution wasstirred for 2 The reaction mixture was poured onto ice and water and2-(a-chlorobutylmercapto) 6-etho:y-.benzothiazole separated as an oilymass.

The above obtained mixture was decanted and the .oil was dissolved inbenzene. The benzene solutionwas concentrated in vacuo, then theoilyconcentrate was dropped onto 300 cc. of chlorosulfonic acid below 10.The mixture was stirred for 3 hours at room temperature, then drowned inice. '2-(oc-chlorobutylmercapto)-6 hydroxybenzothioazole was obtained'as a solid. The mother liquor was decanted off and the solid wasdissolved in alcohol. The alcohol solution was filtered, thenconcentrated in vacuo leaving an oily residue.

The oil was dissolved at 50 in 200 cc. of methanol and 450 cc. ofchlorobenzene. 15 grams of sodium methoxide were added and the mixturewas heated with agitation to 130, allowing the methanol to distill off.30 grams of 8-diethylaminoethyl chloride were added at a temperaturebelow 100 and then the reaction mixture was heated in a reflux condenserfor 4 hours at 131. After cooling to 100, 300 cc. of water and 10 cc. ofsodium hydroxide (40%) were added and the mixture was stirred forone-half hour. The chlorobenzene layer which formed on standing was thenseparated, dried over sodium sulfate and concentrated in vacuo.

The oily2(a-chlorobutylmercapto)-6-(fi-diethylaminoethoxy)-benzothiazole thusobtained as the concentrate was dissolved in 300 cc. of ether, filteredand diluted with ether to a volume of 500 cc. The ether solution waschilled to 5 and 25 cc. of ethanol-HCl (35%) were added. The precipitatewhich formed was filtered, dried in vacuo at 40 and then recrystallizedfrom 500 cc. of acetone and 50 cc. of alcohol. The2-(a-chlorobutylmercapto)-6-(,G-diethylaminoethoxy) benzothiazolehydrochloride melted at l57l59.

Example 12 70 grams of 2-mercapto-6-ethoxy-benzothiazole, 300 cc. ofwater, 60 cc. of sodium hydroxide (40%), 60 grams of n-hexyl bromide and200 cc. of alcohol were refluxed for one hour. The alcohol was distilledoff. The residue was diluted with 300 cc. of water and 2-hexylmercapto-6-ethoxy-benzothiazole separated as an oil.

90 grams of 2-hexylmercapto-6-ethoxy-benzothiazole were dissolved in 800cc. of alcohol. 90 cc. of hydrogen peroxide (30%) were added and thesolution was heated at reflux temperature for 8 hours. The solution wasthen concentrated in vacuo to one-half its volume. The concentrate waspoured into 4 liters of ice water. 2hexylsulfinyl-6-ethoxy-benzothiazole crystallized upon standingovernight in a refrigerator. The crystals were filtered, dried on thefunnel, dried in a desiccator over sulfuric acid and then recrystallizedfrom an n-hexanehydrocarbon fraction, M. P. 7778.

88 grams of 2-hexylsulfinyl-6-ethoxy-benzothiazole were added to 125 cc.of thionyl chloride at a temperature below 20. The solution was stirredfor 2 hours at 15 to 20, then drowned in ice and water. The precipitatewhich formed was dissolved in 200 cc. of alcohol at 75 to 80. Uponstanding in the refrigerator, 2-(uchlorohexylmercapto) 6 ethoxybenzothiazole crystallized, M. P. 50.

50 grams of 2-(u-chlorohexylmercapto)-6-ethoxybenzothiazole weredissolved in 200 cc. of concentrated sulfuric acid at a temperaturebelow 25. The solution was heated for 4 hours at 45 to 50, then slowlydrowned in ice and water. The white precipitate which formed wasfiltered and purified by dissolving the filter cake in 500 cc. of waterand 25 cc. of sodium hydroxide (40%) at room temperature. The solutionwas filtered and the filtrate was acidified with HCl. CrystallineZ-(oc-ChlOIO- hexylmercapto) 6 hydroxy benzothiazole precipitated. Theprecipitate was filtered and dried, M. P. 85.

27 grams of 2-(u-chlorohexylmercapto)-6-hydroxybenzothiazole, 350 cc. ofchlorobenzene, 8 grams of sodium methoxide and 50 cc. of methanol werestirred while heating. The methanol was then distilled oil? until thetemperature of 130 was reached. 20 grams of fl-diethylaminoethylchloride were added at a temperature below 100. The reaction mixture wasrefluxed for 4 hours at 130, then cooled to 100, and diluted with 300cc. of water and cc. of sodium hydroxide. After settling, thechlorobenzene layer was separated and concentrated in vacuo to obtain2-(ct-chlorohexylmercapto)- G-(fi-diethylaminoethoxy) benzothiazole asanoil.

Example 13 225 grams of 2-mercapto-6-ethoxy-benzothiazole were dissolvedin 100 cc. of water and 200 cc. of sodium hydroxide (40%) at roomtemperature. To this solution were added 205 grams of p-chlorobenzylchloride and 4-00 cc. of alcohol. The mixture was heated with agitationfor one hour at reflux temperature. The alcohol was distilled otf andthe residue was diluted with one liter of ice water and stirred for onehour. The crysetalline 2-(p-chlorobenzylmercapto)-6-ethoxy-benzothiazole which formed wasfiltered, washed with water and dried, M. P. to 70.

163 grams of 2-(p-chloro-benzylmercapto)-6-ethoxybenzothiazole wererefluxed with 1000 cc. of alcohol and 150 cc. of hydrogen peroxide for 8hours. After 24 hours, 2-(p-chlorobenzylsulfinyl)-6-ethoxy benzothiazolecrystallized and was filtered oif, M. P. 168-169.

141 grams of 2-(p-chlorobenzylsulfinyl)-6-ethoxy-benzothiazole weredissolved in 250 cc. of thionyl chloride at 20. The solution was stirredfor 2 hours at 20 to 25, then drowned in ice and water. This mixture wasstirred for 4 hours. 2 E(or-chloro)-p-chlorobenzylmercapto]-6-ethoxy-benzothiazole which precipitated was filtered off and dried. Thedry compound thus obtained was dissolved in 500 cc. of sulfuric acid at20-25. The 7 solution was heated at 55 for one hour, then poured ontoice. The 2-[(ix-chloro)-p-ch1orbenzylmercapto]- 6-hydroxy-benzothiazolewhich precipitated was filtered. Upon drying, the product was obtainedas a white powder.

grams of 2-[(ix-chloro)-p-chlorobenzylrnercapto]-6-hydroxy-benzothiazole were condensed with 70 grams of,B-diethylaminoethyl chloride according to the procedure described inExample 1. 2-[(a-chloro)-p-chlorobenzylmercapto] 6 (,3diethylaminoethoxy)benzothiazole was obtained as an oil.

The oily base obtained above was dissolved in 500 cc. of ether andtreated with ethanol-HCl. The 2-[( xchloro) p chlorobenzylmercapto] 6 (Bdiethylaminoethoxy)benzothiazole hydrochloride which precipitated wasrecrystallized from ethanol-acetone and was obtained as white crystals,M. P. 236.

Example 14 g. of 6-ethoXy-Z-mercaptO-benzothiazole were dissolved in 500cc. of water and 100 cc. of sodium hydroxide (40%). A solution of 70 g.sec.butyl bromide in 150 cc. of alcohol was dropped into the solution.The temperature was raised to 80 while stirring for 4 hours. The alcoholwas distilled off. 6-ethoxy-2-sec.-butylmercapto-benzothiazole wasobtained as an oil. grams of 6-ethoxy-2-sec.-butylmercapto-benzothiazolewere dissolved in 500 cc. of methylene chloride and heated to reflux. 70grams of sulfuryl chloride in 100 cc. of methylene chloride were droppedinto the solution at 40 and refluxed for 2 hours. The methylene chloridewas then distilled off. The residue was dissolved in 300 cc. of alcohol.The alcoholic solution was concentrated in vacuo. The concentrate,6-ethoxy-2-(1-chloro-1- methylpropylmercapto) benzothiazole, wasobtained as an oil.

This oil was dropped at room temperature into 600 cc. of concentratedsulfuric acid with stirring which was continued for 4 hours at 50. Themixture was then drowned in ice and water. The 6-hydroxy-2-(1-chloro-1-methylpropylmercapto)benzothiazole thus formed was a heavy oil.

The mother liquor was decanted off and the oil was dissolved in 700 cc.of chlorobenzene and 200 cc. of

methanol. 30 gramsof sodium methoxide wereadded. The mixture wasazeotropically distilled until the temperature of the mass was about131". After cooling to 100, 80 grams of B-diethylaminoethyl chloridewere added. The mixture was heated with stirring at about 130 for 4hours. It was then cooled to 100", 500 cc. of water and 25 cc. of sodiumhydroxide (40%) were added and stirred for one hour. The chlorobenzenelayer was then separated. The 2-(l-chloro-l-methylpropylmercapto) 6 (,3diethylaminoethoxy)benzothiazole in chlorobenzene solution was driedover sodium sulfate, then concentrated in vacuo. The concentrate wasobtained as an oil.

The free base obtained above was dissolved in 600 cc. of acetone andfiltered. To the filtrate was added 'a solution of 70 grams of citricacid in 70 cc. of alcohol. The citrate salt precipitated in crystallineform. Recrystallized from isopropanol, the citrate melted at 130-132".

Example 15 2-amylmercapto-6-ethoxy-benzothiazole was obtained from 80 g.of .n-amyl bromide in 150 cc. of alcohol and 115 g. of2-mercapto-6-ethoxy-benzothiazole dissolved in 500 cc. of water and 100cc. of sodium hydroxide (40%) according to the procedure described inExample 14. This product was chlorinated with 75 grams of sulfnrylchloride in 600 cc. of methylene chloride to obtain 2 (a:chloroamylmercapto)-6-ethoxy-benzothiazole. i

The compound thus obtained was hydrolyzed with 800 cc. of concentratedsulfuric acid to produce Z-(oc-ChlOl'O-amylmercapto)-6-hydroxy-benzothiazole as an oil. The oil was condensedwith 75 g. of fl-diethyIarninOethyl chloride and sodium methoxide inchloro-benzene to ob.- tain2-(a-chloroamylmercapto)-6-(B-diethylaminoethoxy) benzothiazole also asan oil.

The free base obtained above was dissolved in 600 cc. of acetone andstirred with a solution of 70 g. of citric acid in 70 cc. of alcohol.The citrate was crystallized from isopropanol, M. P. 1l8-120.

Example 16 2 (2 rnethylpropylrnercapto) 6 ethoxy benzothiazole wasobtained .from 115 g. of 2-nf ercapto-6- ethoxy-benzothiazole and 75 g.of l-bromo-Z-methylpropane as described in Example 14. it waschlorinated with 70 g. of sulfuryl chloride to yieldZ-(l-chlorO-Z-methylpropylmercapto)-6 ethoxy-benzothiazole. Afterhydrolysis with 725 cc. of concentrated sulfuric acid at 50, there wasobtained 2-(l-chloro-Z-methylpropylmercapto)- fi-hydroxy-benzothiazole.

The compound thus obtained wascondensed with75 g. offi-diethylaminoethyl chloride and 28 g. of sodium methoxide to obtainthefree base, 2-(1-chloro-2-methylpropylmercapto) 6 (3diethylaminoethoxy)benzothiazole, as an oil.

38 g. of the base were dissolved in 200 ccQof acetone.

12 cc. of ethanol-H01 (35%) were added at to ob-,

tain the crystalline hydrochloride salt, M. P. 143-144" (recrystallizedfrom isopropanol) 83 g. of the oily base obtained above were dissolvedin 600 cc. of acetone. To this was added with stirring at 5 a solutionof 46 g. of citric acid in 50 cc. of alcohol. The citrate obtainedmelted at 138-439 upon recrystallization from isopropanol.

Example 1' 7 l 2 (3 methylbntylmercapto) 6 ethoxy benzothiazole wasobtained as an oil from 115 g. of Z-mercapto- 6-ethoxy-benzothiazole and80 g. of 1-bromo-2-methyl butane according to the procedure described inExample 14. This was chlorinatedwith 75 g. of .sulfuryl chloride inmethylene chloridesolution-to obtain 2 l-chloro-3-methylbutylmercapto)-6-ethoxy-benzothiazole. After hydrolysis inconcentrated sulfuric acid, the corresponding oehydroxycompound'obtained was condensed in chloro- 12 benzene withfl-diethylaminoethyl chloride and sodium methoxide to yield2-(1-chloro-3-methylbutylmercapto) 6- 2-diethylaminoethoxy)benzothiazole.

90 g. of the above obtained base in 400 cc. of acetone were filtered. Tothe chilled filtrate were added 25 cc.

of ethanol-H61 (35%). The hydrochloride salt of the abovebasecrystallized, M. P. 139-140 (recrystallized from isopropanol). Thecitrate was obtained according to the procedure described in Example 16,M. P. 135 (recrystallized from ethanol).

Example 18 2-(n-decylmercapto)-6 ethoxy benzothiazole, M. P. 38-39", wasobtained from 70 g. of 2-mercapto-6-ethoxy benzothiazole and 70 g. ofbromo-decane according to the procedure described in Example 14. 97 g.of the thioether was chlorinated in 500 cc. of methylene chloride with42 g. of sulfuryl chloride to obtain crystallineZ-(achlorodecylmercapto)-6-ethoxy-benzothiazole.

71 g. of the above oc-ChlOlO compound'in 350 cc. of concentratedsulfuric acid were stirred at 45 for 5 hours. The mixturewas drowned inice and water. A semisolid mass was obtained. The 6-hydroxy compoundthus obtained was condensed with e-diethylaminoethyl chloride inchlorobenzene (600 cc.) and sodium methoxide. The base,2-(a-chlorodecylmercapto)-6-(;8-dietbylaminoethoxylbenzothiazole, wasobtained as a wax.

. The free base was converted to its dicitrate by heating a solution ofthe wax in acetone with an alcoholic solution of citric acid. Thecrystalline dicitrate melted at 130-134 upon recrystallization fromethanol-acetone.

Example 19 75 g. of 2-(u-chloroethylmercapto)-6-hydroxy-benzothiazole,21 g. of sodium methoxide, 650 cc. of chlorobenzene and cc. of methanolwere heated to The methanol was allowed to distill off. 45g. of'y-dimethylamino-n-propyl chloride were added at 100. This mixture wasrefluxed for 4 hours, then stirred at room temperature for 2 hours with500 cc. of water and 25 cc. of sodium hydroxide (40%). The chlorobenzenelayer was separated and concentrated in vacuo to obtain2-(u-chloroethylmercapto)-6 (1/ dimethylaminopropoxy)benzothiazole.

The free base obtained above was dissolved in 300 cc. of isopropanol. Tothe chilled solution were added 30 cc. of isopropanol-HCl (30%). Thecrystalline hydrochloride thus produced'melted at v This application isa continuation-in-part of my copending application Serial'Number467,890, filed November 9,1954. 7 i I I claim:

1. A compound selected from the group consisting of bases represented bythe formula N R3 7 f o-s-o-n; N-lower alkylene-O- II V S halogen loweralkyl o-s-hmwer sllryl N lower allrylene- S halogen lower alkyl 3.2-chloromethylmercapto-6-(fl-dicthylaminoethoiry)- benzothiazole.

8. A method for producing a 2-(u-ha1oalkylmercapto)-hydroxy-benzothiazole which comprises hydrolyzing a2-(a-haloalkylmercapto) 6 lower alkoxy benzothiazole with a member ofthe group consisting of concentrated sulfuric acid and chlorosulfonicacid.

9. 2-(1-ch1or0-3-methylbutylmercapto)-6 (2 diethylaminoethoxy)benzothiazole.

References Cited in the file of this patent Taniyama: Chem. Abst., vol.45, col. 9530 (1951). Grunberg et aL: Chem. Abst. vol. 47, col 8816v(1953).

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES REPRESENTED BYTHE FORMULA
 2. COMPOUNDS REPRESENTED BY THE FORMULA